by the cell (Zhang et al. 2018). Many natural polysaccharides, namely, chitosan and

hyaluronic acid, offer a biocompatible and non-immunogenic approach in

formulating a siRNA delivery system. Since chitosan possesses a positive charge,

it is capable of reacting with siRNA, leading to the formation of polyplex complexes

which show good stability. Thus, this electrostatic interaction ensures the protection

of the therapeutic siRNA from getting degraded. Hyaluronic acid is anionic and

requires an additional cation to ensure electrostatic reaction with the siRNA mole-

cule. It makes the entire complex stable and improves the targeting efficiency of

siRNA therapeutic (Serrano-Sevilla et al. 2019). Solid lipid nanoparticles contain a

lipid bilayer with a cation and fusogenic lipid mix that ensure uptake by the cell and

endosome-based releasing of siRNA. These nanocarriers can be made stable through

coatings of polyethylene glycol which are successful in providing a hydrophilic

outer shell (Ozpolat et al. 2014). Because cation-based polymers are highly stable

and easy to prepare, they are a preferable coating agent. Many synthetic polymers

have been reported for delivery, namely, polyamino acid, polyethyleneimine, and

polyamidoamine. Inorganic nanocarriers lack amino-containing functional moieties

which favor siRNA delivery. These include gold nanoparticles, nanorods, and

apatite nanocarriers (Meng et al. 2013).

20.3.3 Molecular Mechanisms and Biological Function of siRNA

Nanocarriers in Diabetic Neuropathic Pain

Diabetic neuropathic pain involves a sharp burning and lancinating sensation which

may even be perceived as a shock. This pain starts with moderate intensity and

worsens during night hours which leads to alteration of the sleep cycle and even

insomnia. The constant pain alters the quality of life of the patient. As a result, the

patient undergoes withdrawal from social activity giving rise to depressive

symptoms (Schreiber 2015). siRNA is a double-stranded RNA molecule that causes

interference in the genetic expression of complementary base pairs of mRNA and

results in a knockdown of expression. It contains only 20–25 nucleotide sequences

situated at both ends. These ends undergo binding to cause degradation of the

mRNA molecule. The genetic component involved in pathogenesis is silenced and

inhibition of neuropathic progression prevails. When a siRNA molecule lies inde-

pendently without conjugated associations, it is called a naked siRNA molecule

(Shende and Patel 2019).

Dorsal root ganglion accepts pain signaling from peripherally situated nerves and

transmits them to the central nervous system. Receptors, namely, P2X3 and P2X7,

have been linked with the pathogenesis of central neuropathic pain. While P2X3

resides majorly in the primary sensory neuron, P2X7 is mainly situated in the satellite

glial cells in the dorsal root ganglion. P2X3 elevates nociceptive action by sensitiza-

tion of pain fiber, P2X7 is involved in the purinergic signal pathway of chronic pains.

In a study performed on P2X7 receptor-mediated diabetic neuropathy in rats, BC1

68687 siRNA intrathecal injection was successful in inhibiting the expression of the

causative receptor P2X7. As a result, the pathology of diabetic neuropathy was

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